The Accumulation of Mestranol and Ethynyloestradiol Metabolites in the Organism

Abstract

1. Following a single intravenous administration of [6,7–³H]ethynyloestradiol and [6,7–³H]mestranol to female rats, 55% of the labelling was excreted in the faeces within 3 weeks, whereas only small amounts of radioactivity (1.5%) were recovered from urine during the first 3 days. These values for both drugs contrast markedly to the overall recovery rate of [4–¹⁴C]oestradiol (75% in 3 days).

2. The lipophilic properties of mestranol lead to an excretion pattern different from that of ethynyloestradiol. After 24 h, 19% of the mestranol radioactivity was retained and then released gradually until the 10th day after administration.

3. Accumulation of the radioactivity of [4–¹⁴C]oestradiol, [6,7–³H]ethynyloestradiol and [6,7–³]mestranol under chronic treatment (2.5 μg daily for 19 days) was studied in brain, lung and liver of mice. Compared with oestradiol, ethynyloestradiol and mestranol caused 2–3-fold higher levels of radioactivity in these organs. After ending administration, the radioactivity of ethynyloestradiol and mestranol disappeared within 4 days. Comparison with previous findings for a single dose gives evidence that accumulation of metabolic products occurs during treatment with ethynyloestradiol or mestranol.

4. In contrast to [4–¹⁴C]oestradiol, radioactivity in the liver during chronic treatment with [6,7–³H]ethynyloestradiol or [6,7–³H]mestranol was tightly bound to tissue and could not be removed by solvent extraction or hot acid hydrolysis, suggesting that these latter compounds are converted to metabolites which differ considerably from those arising from the natural hormone oestradiol.

5. The high demethylation rate of [methoxy-³H]mestranol in mice (60.9±0.7%) compared with that of rats (34.5±1.2%, as determined previously) is due to the 2- to 4-fold higher activity of the microsomal mixed function oxidase in the liver of mice.